Clinical pharmacology

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%.

Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the blue tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of desogestrel/ethinyl estradiol and ethinyl estradiol combination tablets [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [blue] is 99%. The effect of food on the bioavailability of Azurette tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Azurette tablets were determined during the third cycle in 17 subjects. Plasma concentrations of etonogestrel and ethinyl estradiol reached steady-state by Day 21. The AUC(0–24) for etonogestrel at steady-state on Day 21 was approximately 2.2 times higher than AUC(0–24)on Day 1 of the third cycle. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Azurette tablets are summarized in Table I.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL/ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=17)

Etonogestrel

Day

Dose† mg

Cmax pg/mL

Tmax h

t ½ h

AUC0–24 pg/mL•hr

CL/F L/h

1

0.15

2503.6 (987.6)

2.4 (1.0)

29.8 (16.3)

17,832 (5674)

5.4 (2.5)

21

0.15

4091.2 (1186.2)

1.6 (0.7)

27.8 (7.2)

39,391 (12,134)

4.4 (1.4)

†Desogestrel

Ethinyl Estradiol

Day

Dose mg

Cmax pg/mL

Tmax h

t ½ h

AUC0–24 pg/mL•hr

CL/F L/h

1

0.02

51.9 (15.4)

2.9 (1.2)

16.5 (4.8)

566 (173)a

25.7 (9.1)

21

0.02

62.2 (25.9)

2 (0.8)

23.9 (25.5)

597 (127) a

35.1 (8.2)

24

0.01

24.6 (10.8)

2.4 (1.0)

18.8 (10.3)

246 (65)

43.6 (12.2)

28

0.01

35.3 (27.5)

2.1 (1.3)

18.9 (8.3)

312 (62)

33.2 (6.6)

a n=16

Cmax – measured peak concentration

Tmax – observed time of peak concentration

t½ – elimination half-life, calculated by 0.693/Kelim

AUC0–24 – area under the concentration-time curve calculated by the linear trapezoidal rule (Time 0 to 24 hours)

CL/F – apparent clearance

Distribution

Etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is approximately 98.3% bound, mainly to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96–99).

Metabolism

Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. Other metabolites (i.e., 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) with no pharmacologic actions also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Excretion

Etonogestrel and ethinyl estradiol are excreted in urine, bile, and feces. At steady state, on Day 21, the elimination half-life of etonogestrel is 27.8 ± 7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9 ± 25.5 hours. For the 0.01 mg ethinyl estradiol tablet [blue], the elimination half-life at steady state, Day 28, is 18.9 ± 8.3 hours.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) tablets .33

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Azurette.

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of Azurette.

Drug-Drug Interactions

Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted (see PRECAUTIONS section).

Indications and usage

Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective. Table II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used.Correct and consistent use of these methods can result in lower failure rates.

TABLE II: Percentage of women experiencing an unintended pregnancy during the firs t year of typical use and the firs t year of perfect use of contraception and the percentage continuing use at the end of the firs t year, United States

% of Women Experiencing an Accidental Pregnancy within the First Year of Use

% of Women Continuing Use at One Year3

Method (1)

Typical Use1 (2)

Perfect Use2 (3)

(4)

Chance4

85

85

Spermicides 5

26

6

40

Periodic abstinence

25

63

Calendar

9

Ovulation method

3

Sympto-thermal 6

2

Post-ovulation

1

Post-ovulation

19

4

Cap7

Parous women

40

20

42

Nulliparous women

20

9

56

Sponge

Parous women

40

20

42

Nulliparous women

20

9

56

Diaphragm 7

20

6

56

Condom 8

Female (Reality)

21

5

56

Male

14

3

61

Pill

5

71

Progestin only

0.5

Combined

0.1

IUD

Progesterone T 2.0

2.0

1.5

81

Copper T380A

0.8

0.6

78

Lng 20

0.1

0.1

81

Depo-Provera

0.3

0.3

70

Norplantand Norplant-2

0.05

0.05

88

Female sterilization

0.5

0.5

100

Male sterilization

0.15

0.10

100

Adapted from Hatcher et al., 1998, Ref#1.

Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the firsy year if they do not stop use for any other reason.

Among couples who initiate use of a method (not necessarily for thr first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any reason.

Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.

The percents becoming pregnant in columns (2) and (3) are based on data from populations where contrsception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.

Foams, creams, gels, vaginal suppositories, and vaginal film.

Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.

With spermicidal cream or jelly.

Without spermicides.

Contraindications

Oral contraceptives should not be used in women who currently have the following conditions:

Thrombophlebitis or thromboembolic disorders

A past history of deep vein thrombophlebitis or thromboembolic disorders

Cerebral vascular or coronary artery disease

Known or susected carcinoma of the breast

Carcinoma of the endometrium or other known or sected estrogen-dependent neoplasia

Undiagnosed abnormal genital bleeding

Cholestatic jaundice of pregnancy or jaundice with prior pill use

Hepatic adenomas or carcinomas

Known or susected pregnancy

Warning

Cigarette smoking increases the risk of serious cardiovascular s ide effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among non-users. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and non-users. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiologic methods.

Thromboembolic Disorders and Other Vascular Problems

Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thromboembolic disease, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease (2,3,19–24). Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (25). The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped (2).

Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (102–104). In general, these studies indicate an approximate two- fold increased risk, which corresponds to an additional 1 to 2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk.

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives (9,26). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (9,26). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed.

Myocardial infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (4–10). The risk is very low in women under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases (11). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, over the age of 35 and non-smokers over the age of 40 (Table III) among women who use oral contraceptives.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (13). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (14–18). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Cerebrovascular diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and non-users, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (27–29).

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (30). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension (30). The attributable risk is also greater in older women (3).

Dose-related risk of vascular disease from oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (31–33). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (14–16). A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing 0.035 mg or less of estrogen.

Persistence of risk of vascular disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups (8). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small (34). However, both studies were performed with oral contraceptive formulations containing 50 micrograms or more of estrogen.

Estimates of Mortality From Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table IV). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s - but not reported until 1983 (35). However, current clinical practice involves the use of lower estrogen formulations combined with careful consideration of risk factors.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (100,101), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

TABLE IV: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDINGTO AGE

Method of Control and Outcome

AGE

15 to 19

20 to 24

25 to 29

30 to 34

35 to 39

40 to 44

No fertility control methods*

7.0

7.4

9.1

14.8

25.7

28.2

Oral contraceptives nonsmoker**

0.3

0.5

0.9

1.9

13.8

31.6

Oral contraceptives smoker**

2.2

3.4

6.6

13.5

51.1

117.2

lUD**

0.8

0.8

1

1

1.4

1.4

Condom*

1.1

1.6

0.7

0.2

0.3

0.4

Diaphragm/ spermicide*

1.9

1.2

1.2

1.3

2.2

2.8

Periodic abstinence*

2.5

1.6

1.6

1.7

2.9

3.6

Adapted from H.W. Ory, ref.#35

* Deaths are birth-related

** Deaths are method-related

Carcinoma of the Reproductive Organs and Breasts

Numerous epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. While there are conflicting reports, most studies suggest that the use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer. Some studies have reported an increased relative risk of developing breast cancer, particularly at a younger age. This increased relative risk appears to be related to duration of use (36–43, 79–89).

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intra-epithelial neoplasia in some populations of women (45–48). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

Hepatic Neoplasis

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose (49). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (50,51).

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (52–54) in long-term (> 8 years) oral contraceptive users. However, these cancers are extremely rare in the US and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

Oral Contraceptive Use Before or During Early Pregnancy

Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (55–57). Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned (55,56,58,59), when oral contraceptives are taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the first missed period. Oral contraceptive use should be discontinued until pregnancy is ruled out.

Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (60,61). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (62–64). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users (17). Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (65). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (17,66). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

Elevated Blood Pressure

An increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase is more likely in older oral contraceptive users (69) and with continued use (61). Data from the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (69), and there is no difference in the occurrence of hypertension between ever- and never-users (68,70,71).

Headache

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Precautions

GENERAL

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

PHYSICAL EXAMINATION AND FOLLOW UP

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

LIPID DISORDERS

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

LIVER FUNCTION

If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

FLUID RETENTION

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

EMOTIONAL DISORDERS

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

CONTACT LENSES

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

DRUG INTERACTIONS

Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, carbamazepine and possibly with griseofulvin, ampicillin, and tetracyclines (72).

INTERACTIONS WITH LABORATORY TESTS

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged.

High-density lipoprotein cholesterol (HDL-C) and triglycerides may be increased, while low- density lipoprotein cholesterol (LDL-C) and total cholesterol (Total-C) may be decreased or unchanged.

Glucose tolerance may be decreased.

Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

CARCINOGENESIS

See WARNINGS section.

PREGNANCY

Pregnancy Category X (see CONTRAINDICATIONS and WARNINGS sections).

NURSING MOTHERS

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

PEDIATRIC USE

Safety and efficacy of Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

INFORMATION FOR THE PATIENT

See Patient Labeling Printed Below

Adverse reactions

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

Thrombophlebitis and venous thrombosis with or without embolism

Cerebral hemorrhage

Cerebral thrombosis

Arterial thromboembolism

Hypertension

Pulmonary embolism

Gallbladder disease

Myocardial infarction

Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives:

Mesenteric thrombosis

Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

Nausea

Change in weight (increase or decrease)

Vomiting

Change in cervical erosion and secretion

Gastrointestinal symptoms (such as abdominal cramps and bloating)

Diminution in lactation when given immediately postpartum

Breakthrough bleeding

Cholestatic jaundice

Spotting

Migraine

Change in menstrual flow Rash (allergic)

Amenorrhea

Mental depression

Temporary infertility after discontinuation of treatment

Reduced tolerance to carbohydrates

Vaginal candidiasis

Edema

Change in corneal curvature (steepening)

Melasma which may persist

Intolerance to contact lenses

Breast changes: tenderness, enlargement, secretion

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

Pre-menstrual syndrome

Erythema nodosum

Cataracts

Hemorrhagic eruption

Changes in appetite

Vaginitis

Cystitis-like syndrome

Porphyria

Headache

Impaired renal function

Nervousness

Hemolytic uremic syndrome

Dizziness

Acne

Hirsutism

Changes in libido

Loss of scalp hair Colitis

Erythema multiforme

Budd-Chiari

Syndrome

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

NON-CONTRACEPTIVE HEALTH BENEFITS

The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiologic studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (73–78).

decreased incidence of fibroadenomas and fibrocystic disease of the breast

decreased incidence of acute pelvic inflammatory disease

decreased incidence of endometrial cancer

decreased incidence of ovarian cancer

Dosage and administration

To achieve maximum contraceptive effectiveness, Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) tablets must be taken exactly as directed and at intervals not exceeding 24 hours. Azurette may be initiated using either a Sunday start or a Day 1 start.

NOTE: Each tablet dispenser is preprinted with the days of the week, starting with Sunday, to facilitate a Sunday start regimen. Six different “day label strips” are provided with each tablet dispenser in order to accommodate a Day 1 start regimen. In this case, the patient should place the self-adhesive “day label strip” that corresponds to her starting day over the preprinted days.

IMPORTANT: The possibility of ovulation and conception prior to initiation of use of Azurette should be considered.

The use of Azurette for contraception may be initiated 4 weeks postpartum in women who elect not to breast feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS for “Nursing Mothers”).

If the patient starts on Azurette postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a white tablet has been taken daily for 7 days.

SUNDAY START

When initiating a Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration.

Using a Sunday start, tablets are taken daily without interruption as follows: The first white tablet should be taken on the first Sunday after menstruation begins (if menstruation begins on Sunday, the first white tablet is taken on that day). One white tablet is taken daily for 21 days, followed by 1 green (inert) tablet daily for 2 days and 1 blue (active) tablet daily for 5 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day (Sunday) after taking the last blue tablet. [If switching from a Sunday Start oral contraceptive, the first Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) tablet should be taken on the second Sunday after the last tablet of a 21 day regimen or should be taken on the first Sunday after the last inactive tablet of a 28 day regimen.

If a patient misses 1 white tablet, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. If the patient misses 2 consecutive white tablets in the third week or misses 3 or more white tablets in a row at any time during the cycle, the patient should keep taking 1 white tablet daily until the next Sunday. On Sunday the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back- up method of birth control if she has intercourse in the 7 days after missing pills.

DAY 1 START

Counting the first day of menstruation as “Day 1,” tablets are taken without interruption as follows: One white tablet daily for 21 days, one green (inert) tablet daily for 2 days followed by 1 blue (ethinyl estradiol) tablet daily for 5 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day after taking the last blue tablet. [If switching directly from another oral contraceptive, the first white tablet should be taken on the first day of menstruation which begins after the last ACTIVE tablet of the previous product.]

If a patient misses 1 white tablet, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills. If the patient misses 2 consecutive white tablets in the third week or if the patient misses 3 or more white tablets in a row at any time during the cycle, the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after missing pills.

ALL ORAL CONTRACEPTIVES

Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, non- functional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If both pregnancy and pathology have been excluded, time or a change to another preparation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.

Use of oral contraceptives in the event of a missed menstrual period:

If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued until pregnancy is ruled out.

If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.

How supplied

Azurette® (desogestrel/ethinyl estradiol and ethinyl estradiol) tablets contain 21 round white tablets, 2 round green tablets, and 5 round blue tablets in a dispenser. Each white tablet is round, unscored, debossed with WATSON on one side and 942 on the other side, and contains 0.15 mg desogestrel and 0.02 mg ethinyl estradiol. Each green tablet is round, unscored, debossed with WATSON on one side and P on the other side, and contains inert ingredients. Each blue tablet is round, unscored, debossed with WATSON on one side and 941 on the other side, and contains 0.01 mg ethinyl estradiol.